Functional analysis of the ciliary protein transport regulating kinase ICK in retinal photoreceptor cells

Abstract

Purpose : The abnormalities of cilia formation and maintenance including intraflagellar transport (IFT), the bidirectional protein trafficking of IFT particles along ciliary microtubules, cause human diseases termed ciliopathies, which are characterized by a wide range of symptoms such as developmental and sensory abnormalities. Our and others’ previous studies demonstrated that male germ cell-associated kinase (MAK) and intestinal cell kinase (ICK), also known as ciliogenesis-associated kinase 1 (CILK1), localizes at the tip of cilia as a regulator of ciliary length and/or ciliary protein transport. ICK variants are associated with not only developmental disorders, but also juvenile myoclonic epilepsy; however, the functional roles of ICK in the central nervous system (CNS) remain unclear.

Methods : In order to investigate the roles of ICK in the CNS, we evaluated the effects of Ick deficiency in the retina on IFT and the survival of retinal photoreceptor cells. We generated Ick conditional knockout (CKO) mice, and then performed histological and electrophysiological analyses.

Results : We immunostained rod and cone outer segments and several IFT components in the Ick CKO retina at 1 month (1M), and found no obvious differences were observed between the control and Ick CKO retinas. We also carried out histological analyses of Ick CKO mice at 6 months (6M). Ick CKO mice exhibited decreased outer nuclear layer thickness. In addition, we measured the electroretinograms (ERGs) of Ick CKO mice at 1M and 6M. Light responses in Ick CKO mice were lower than those in the control mice at 6M but not at 1M. Taken together, these results show that the loss of Ick does not affect retinal photoreceptor development but leads to slowly progressive photoreceptor degeneration.

Conclusions : Given that conventional Ick knockout mice exhibit neonatal lethality accompanied with developmental abnormalities observed in multiple organ systems, Ick deficiency caused the milder phenotypes in the retina than expected. These results suggest that redundant genes are likely to function with Ick in the regulation of IFT in the retina. The current study may advance our understanding of molecular mechanisms underlying the regulation of ciliary protein transport in the CNS and the pathogenesis of ciliopathies.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.